PROJECT SUMMARY/ABSTRACT Natural products and natural product derivatives continue to play a prominent role in the discovery and development of pharmaceuticals to treat human diseases. In nearly all instances, the critical barrier to the evaluation, modification, and application of natural products as drugs is accessibility. Specific to this proposal, consider the recently discovered phainanoid natural products. This new class of structurally-complex triterpenoids has demonstrated extremely potent immunosuppressive activity with IC50 values in single-digit nanomolar concentrations (prior to any medicinal chemistry-inspired modification/improvement). The so-called phainanoid F, in particular, is 7 and 221 times more active against the proliferation of T and B cells, respectively, than cyclosporine A ? a commercial immunosuppressant notably on the WHO's List of Essential Medicines. Thus, it is evident that the phainanoids could represent promising and insightful lines of inquiry for the development of a new class of immunosuppressive drugs; however, further investigation is currently hindered by the aforementioned problem of accessibility. One viable solution to this problem is a concise, efficient total synthesis strategy that is ideally amenable to various late-stage modifications for medicinal chemistry. Accordingly, the specific aims of this proposal are 1) to develop a strategy for a practical total synthesis of phainanoids A-F and 2) to create avenues for late-stage modifications of the phainanoids in order to study structure-activity relationships. The total synthesis strategy proposed herein seeks to obtain the phainanoids in as little as 18- to 21-step longest linear sequences, and it employs several modern synthetic methods in order to maximize efficiency, scalability, and step savings. Among these are cutting-edge decarboxylative olefination tactics, electrochemical oxidations, photochemical rearrangements, catalysis, and directed C-H functionalization chemistry, as well as a proposed opportunity for method development (i.e. an intramolecular decarboxylative olefination variant). Furthermore, the synthesis is designed such that the unique spirocyclic motifs on the phainanoid carbon skeleton strategically are installed very late in the sequence, as these are believed, in large part, to be most responsible for the observed biological activity. Considering there is preliminary evidence for dramatic influence of the spirolactone segment on immunosuppressive activity, special attention is paid to its independent synthesis/installation. Thus, a successful execution of this synthesis will open up a door for rapid and easy diversification of the phainanoids (e.g. employing contemporary fluorofunctionalization tactics), and subsequently all derivatives will be tested for activity in collaboration with an immunology laboratory. In all, this will allow efficient analysis of structure-activity relationships and, hopefully, provide insight as to how to improve the phainanoids as potential immunosuppressive drug candidates.